History of Schizophrenia Research

Schizophrenia is a severe brain disorder that causes hallucinations, delusions (unshakable false beliefs that may be bizarre), and serious cognitive impairments that often lead to disability. Prior to the discovery of antipsychotic medications, many patients with schizophrenia spent years in hospitals. Although medications do not treat all symptoms and have significant side effects, their use, along with psychosocial treatments, now allows most people to lead independent lives. A wide variety of antipsychotic drugs have been developed through animal research.

The very first antipsychotic drug, chlorpromazine, was found to treat hallucinations and delusions based on serendipitous observations in humans. The ability to develop new drugs began with the side effects of chlorpromazine. Scientists noticed issues such as tremor and stiffness with chlorpromazine - symptoms similar to in Parkinson's disease - and wondered if there was a common factor. Using rats, Nobel Prize winner Arvid Carlsson discovered that a neurotransmitter called dopamine was involved. He noted that the side effects of chlorpromazine and the symptoms of Parkinson's disease both result from a decrease of dopamine. The realization that decreasing dopamine helped alleviate psychotic symptoms lead to the development of medications with milder side effects. Investigations into dopamine's role in schizophrenia have led to relatively effective treatments for the positive symptoms of schizophrenia - hallucinations and delusions. However, current treatments are less likely to improve the negative symptoms - such as the loss of drive and pleasure - or the cognitive symptoms - impairments in memory, decision making, and focus. Recent discoveries, including genetic work, have shown that other neurotransmitters and neuromodulators play an important role in those symptoms. Schizophrenia is heritable. There is no single gene for schizophrenia. Rather, many genes interact to produce risk of this disorder. One of the most important models in which to study schizophrenia-risk genes is in the mouse brain. In recent years, scientists have identified more than fifty genes associated with an increased risk for schizophrenia. They have begun to study what these genes do in order to develop a new generation of treatments.

A surprising connection between this genetic work and drugs of abuse has focused recent research on the neurotransmitter glutamate. After scientists realized the illicit drug phencyclidine (PCP) could trigger schizophrenia-like symptoms in humans, animal research showed the PCP blocked a receptor for glutamate. Additionally, a number of the schizophrenia-risk genes affect glutamateric signaling, a fact important during development, indicating the harm from these mutations could begin early in life.

Since the glutamatergic deficit seems to drive negative and cognitive symptoms, scientists hope that continued animal research will help in the development of treatments able to target all of the symptoms. Eventually, scientists hope to understand and treat the underlying causes of schizophrenia.